Congenital Hypothyroidism

Evaluating a patient for congenital hypothyroidism (CH)

With rare exceptions, the majority of patients with congenital hypothyroidism will be diagnosed based on an abnormal newborn screen. The most common etiology is abnormal development or function of the thyroid gland. These disorders are described under the category of:

Primary Hypothyroidism, with the potential causes including:

  • Dysgenesis/Agenesis – abnormal formation of the thyroid gland.

  • Ectopic thyroid – abnormal location/migration of the thyroid gland.

  • Dyshormonogenesis – the inability to produce thyroid hormone in an otherwise normally positioned thyroid gland.

  • Drug or antibody induced (maternal) – block of thyroid hormone production from a thyroid-hormone receptor blocking antibody or medicine that the mother produced or ingested and which crossed the placenta to affect the baby’s ability to produce thyroid hormone. In contrast to the other forms of primary hypothyroidism, this process is usually transient, resolving after weeks or months.

Central (Secondary) Hypothyroidism – lack of thyroid hormone due to inadequate secretion of thyrotropin (TSH) from the pituitary. This is usually associated with multiple pituitary hormone deficiencies.

Tertiary Hypothyroidism – lack of thyroid hormone secondary to inadequate secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus. Also typically associated with multiple pituitary hormone deficiencies.


The majority of infants (95%) do not have obvious manifestations, emphasizing the importance of routine newborn screening. Symptoms and signs likely to increase with time may include lethargy, difficulty waking for feeds, constipation, dry skin, difficulty feeding or gaining weight, temperature lability, and hyperbilirubinemia.

Physical Exam

Birth weight and length are typically within the normal range for gestational age. Head circumference may be larger secondary to cerebral myxedema. Other findings may include large fontanelle(s), macroglossia (enlarged tongue), hoarse cry, hypotonia or umbilical hernia.

Key laboratory findings

Clinical diagnosis is difficult secondary to a lack of signs and symptoms, therefore newborn screening programs have been implemented in all 50 States and many developed countries. A low thyroxine (T4) and elevated TSH are consistent with a diagnosis of congenital hypothyroidism. Blood screening by venipuncture or heel-stick on filter cards is ideally collected at day of life 2-5. States use one of three major screening strategies, either T4, TSH or TSH/T4 combination. State specific testing information and contact information can be found at the National Newborn Screening and Genetics Resources Center ( There has been a fair amount of discussion whether repeat newborn screening (including hypothyroid screening) may be performed at 2 weeks of age in order to improve sensitivity and specificity of testing. Check with your State to determine whether this is recommended.

What else could the patient have?

In order to accurately interpret the TSH and T4 levels, one must consider the age and clinical status of the patient. Healthy, term infants have a rise in TSH at the time of delivery (TSH surge). The TSH subsequently decreases over the next few days typically settling into a normal range by 2 weeks of life. With this in mind, for accurate interpretation, one must verify the time that the sample was drawn.

Special considerations for preterm (low or very low birth weight; LBW or VLBW), and/or acutely ill infants must be used. Premature birth is associated with a delayed and attenuated TSH surge. In this age group an elevated TSH is usually reflective of true disease. A low TSH is more difficult to interpret whether it is secondary to prematurity or potential confounding variables including acute illness (‘euthyroid sick syndrome’ or non-thyroidal illness) or medications that suppress the hypothalamic-pituitary-thyroid axis (ie. dopamine).

Key laboratory and imaging tests

The differential diagnoses of potential laboratory results are:

  • Low serum T4 and elevated TSH – most like primary hypothyroidism.

  • Normal serum T4 and elevated TSH – may be transient, compensated hypothyroidism or permanent hypothyroidism. Need to follow with repeat testing to distinguish between delayed or abnormal hypothalamic-pituitary-thyroid axis function.

  • Low serum T4 and normal TSH – hypothalamic immaturity, maternal iodine deficiency, prematurity, maternal antithyroid drugs, maternal thyroid antibodies, protein-binding disturbances (TBG deficiency), medication side effect (i.e. dopamine or high-dose glucocorticoids), or central hypothyroidism.

  • Low T4/Delayed TSH Increase – Transient hypothyroidism, abnormal pituitary-thyroid feedback, or dyshormonogenesis.

Less commonly, babies may present outside of the typical age of diagnosis. This may be due to maternal T4 which crosses the placenta and provides protection for up to 3-4 weeks (maternal T4 halflife is 6 days) or a dysgenetic (displaced, malpositioned or underdeveloped) gland that is unable to maintain adequate thyroid hormone production with increasing age and size of the baby.

Other tests that may prove helpful diagnostically

The most important point to remember is that if there is any concern over the possibity of congenital hypothyroidism thyroid hormone replacement therapy should be initiated immediately, even before the results of confirmatory testing are back. A serum TSH and free T4 are the most frequently ordered confirmatory tests. The goal of therapy is to normalize thyroid hormone levels within 2 weeks of initiating therapy.

If there is a history of maternal autoimmune thyroid disorder, consider sending thyroid receptor antibodies (TRAb) from the mother, cord blood or infant in addition to TSH/T4. The risk of maternal-induced fetal thyroid dysfunction is most typically associated with maternal Graves’ disease, due to the thyroidal stimulatory effect of TRAb on the fetus resulting in neonatal Graves’ disease. However, maternal TRAb may have a blocking effect leading to transient or permanent hypothyroidism in the baby.

Imaging is controversial given the unclear utility that it provides in deciding on acute management (i.e. whether thyroid hormone replacement should be started):

  • Ultrasound (US) is useful to assess if there is an orthotopically (normally) positioned thyroid gland.

  • 123I or 99mTc thyroid uptake scan is useful to identify whether there is functional thyroid tissue and the location of ectopic thyroid tissue if ultrasound does not identify a normally positioned thyroid gland. If the scan does not reveal a normally positioned or formed thyroid gland this may allow for determination and counseling over the need for long-term thyroid hormone replacement. The presence of blocking TRAb may also be associated with a negative scan.

Management and treatment of the disease

The goal is to initiate treatment as soon as possible, ideally within the first 1-2 weeks of life. Optimal cognitive outcome depends on the timing and adequacy of postnatal therapy.

Initiate levothyroxine (LT4) at 10-15mcg/kg/day:

  • Split/crush tablets and mix with water, expressed breast-milk or formula.

  • There are no stable forms of LT4 suspension produced in the United States.

  • Suspensions must be avoided.

  • Place on a teaspoon, draw up in syringe or dropper and squirt into the baby’s mouth, against the cheek pad.

  • Do NOT place the dose in the bottle if the infant is formula fed because there is no way to determine or ensure if the baby will receive the entire dose. Also, LT4 may adhere to the surface of the bottle, resulting in decreased absorption.

  • Optimum absorption occurs on an empty stomach, but this is difficult in infants. Therefore, consistent timing and method of administration is most important.

  • Do not give thyroid hormone replacement therapy at the same time with soy, iron, calcium or fiber because this decreases absorption. Simethicone may also reduce absorption of thyroid hormone.


Recheck serum TSH and free T4 (FT4) or T4 in 2-4 weeks after the initial treatment is started. Repeat every 1-2 months in the first 6 months, every 3-4 months in first 6 months to 3 years, then every 6-12 months from 3 years to growth is completed.

Goals of therapy

  • Normalize TSH within 30 days and maintain FT4 in the upper half of the reference range throughout therapy. Adjust the dose to maintain these goals.

  • Consider assessment of permanence of disease at age 3 years of age.

  • If the TSH remains normal on treatment despite no increase in the dose of thyroid hormone replacement consider a trial off of therapy at 3 years of age. If the thyroid hormone is stopped, recheck TSH and FT4 in 4-6 weeks. A significant increase in TSH with a low FT4 is suggestive or consistent with permanent hypothyroidism and thyroid hormone replacement should be restarted.

There is evidence to suggest an increased incidence of cardiac and renal anomalies in patients with severe CH. However, to date, there is no consensus on whether universal radiological screening (echocardiogram and/or renal ultrasound) should be performed.

Algorithm for the abnormal newborn screen – see Figure 1

Figure 1.n

Algorithm for Abnormal Newborn Screen

What’s the Evidence?/References

Rose, SR, Brown, RS. ” Update of Newborn Screening and Therapy for Congenital Hypothyroidism”. Pediatrics. vol. 117. 2006. pp. 2290(Latest AAP release on newborn screening for CH and management.)

LaFranchi, SH. ” Approach to the Diagnosis and Treatment of Neonatal Hypothyroidism”. J Clin Endocrinol Metab. vol. 96. Oct 2011. pp. 2959-67. (Updated guidelines/algorithm for the treatment of CH.)

Counts, D, Varma, SK. ” Hypothyroidism in Children”. Pediatrics in Review. . vol. 30. 2009. pp. 251(Overview of CH from general pediatric perspective.)

LaFranchi, SH. ” Newborn screening strategies for congenital hypothyroidism: an update”. J Inher Metab Dis. vol. 33. 2010. pp. S225-S233. (Overview/update on current newborn screening practices in U.S.)

Kumar, J, Gordillo, R, Kaskel, FJ, Druschel, CM, Woroniecki, RP. “Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism”. J Pediatr.. vol. 154. 2009. pp. 263(Highlights increased incidence of GU anomalies in CH.)

Olivieri, A, Stazi, MA, Mastroiacovo, P, Fazzini, C, Medda, E, Spagnolo, A, DeAngelis, S, Grandolfo, ME, Taruscio, D, Cordeddu, V. “A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (1991-1998)”. JClinEndocrinolMetab.. vol. 87. 2002. pp. 557-62. (Highlights increased incidence of congenital anomalies that should be screened with CH.)

Selva, KA, Harper, A, Downs, A, Blasco, PA, Lafranchi, SH. ” Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH”. J Pediatr.. vol. 147. 2005. pp. 775(Justifies treatment recommendations to optimize neurodevelopmental outcomes in CH.)

LaFranchi, SH, Austin, J. “How should we be treating children with congenital hypothyroidism”. J Pediatr Endocrinol Metab.. vol. 20. 2007. pp. 559(Review of suggested treatment algorithms and how current dose recommendation is supported.)

Counts, D, Varma, SK. ” Hypothyroidism in Children”. Pediatrics in Review. . vol. 30. 2009. pp. 251(Overview of CH from general pediatric perspective.)

LaFranchi, SH. ” Newborn screening strategies for congenital hypothyroidism: an update”. J Inher Metab Dis. vol. 33. 2010. pp. S225-S233. (Overview/update on current newborn screening practices in U.S.)